Polygenic dissection of major depression clinical heterogeneity

Abstract

The molecular mechanisms underlying Major Depressive Disorder (MDD) are largely unknown. Limited success of previous genetics studies may be attributable to heterogeneity of MDD, aggregating biologically different subtypes. We examined the polygenic features of MDD and two common clinical subtypes (typical and atypical) defined by symptom profiles in a large sample of adults with established diagnoses. Data were from 1,530 patients of the Netherlands Study of Depression and Anxiety (NESDA) and 1,700 controls mainly from the Netherlands Twin Register (NTR). Diagnoses of MDD and its subtypes were based on DSM-IV symptoms. Genetic overlap of MDD and subtypes with psychiatric (MDD, bipolar disorder, schizophrenia) and metabolic (BMI, C-reactive protein, triglycerides) traits was evaluated via genomic profile risk scores (GPRS) generated from meta-analysis results of large international consortia. SNP-heritability of MDD and subtypes was also estimated. MDD was associated with psychiatric GPRS, while no association was found for GPRS of metabolic traits. MDD subtypes had differential polygenic signatures: typical was strongly associated with schizophrenia GPRS (OR=1.54, p=7.8e-9), while atypical was additionally associated with BMI (OR=1.29, p=2.7e-4) and triglycerides (OR=1.21, p=0.006) GPRS. Similar results were found when only the highly discriminatory symptoms of appetite/weight to were used to define subtypes. SNP-heritability was 32% for MDD, 38% and 43% for subtypes with, respectively, decreased (typical) and increased (atypical) appetite/weight. In conclusion, MDD subtypes are characterized by partially distinct polygenic liabilities and may represent more homogeneous phenotypes. Disentangling MDD heterogeneity may help the psychiatric field moving forward in the search for molecular roots of depression.

Beyond Lumping and Splitting: A Review of Computational Approaches for Stratifying Psychiatric Disorders

“…The disorder with the most consistent stratifications across studies is major depression, where many (53, 54, 55, 56), but not all (57, 58, 59) studies report evidence for “typical” (melancholic) and “atypical” subtypes, although these often do not align with the classical DSM subtypes (60). In contrast, stratifications of schizophrenia, ADHD, and autism have been much more variable across studies.…”

Is a Polygenic Predictor of Antidepressant Response a Possibility?

“…The genetics of MDD is very heterogeneous compared with other psy chiatric disorders as SNP correlation was demonstrated to be slightly above 50% between independent MDD samples and over 80% between independent schizo phrenia samples [14]. Consistently, the partitioning of MDD in different clinical subtypes such as typical and atypical MDD was demonstrated to improve the pre dictive performance of PRS [15] and a similar approach could be useful for antidepressant efficacy. Different MDD subtypes were demonstrated to have different outcomes of antidepressant treatment, for example, chronic MDD or anxious MDD were demonstrated to be particularly at risk of treatment failure [16].…”

Post‐GWAS in Psychiatric Genetics: A Developmental Perspective on the “Other” Next Steps

“…Heterogeneity in symptoms, course, and etiology of disorders is recognized as a profound challenge in studying psychopathology (Dacquino et al , 2015, Geschwind & Flint, 2015, Hines et al , 2005, Lee et al , 2016, Milaneschi et al , 2016, Wium-Andersen et al , 2017). Although this challenge makes gene identification a particularly difficult undertaking, it is hypothesized to be overcome by “brute force” approaches with large sample sizes, as described above (e.g.…”